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J Thorac Cardiovasc Surg 2007;134:1443-1452
© 2007 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology |
a Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Canada
b Division of Cardiovascular Anesthesia, University of Ottawa Heart Institute, Ottawa, Canada.
Read at the Eighty-seventh Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 4-9, 2007.
Received for publication March 20, 2007; revisions received July 18, 2007; accepted for publication August 15, 2007. * Address for reprints: Howard J. Nathan, MD, H341, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7 Canada. (Email: hnathan{at}ottawaheart.ca).
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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Methods: Patients (aged 
60 years) undergoing non-urgent coronary surgery were randomized to an intraoperative nasopharyngeal temperature of 34°C (hypothermic; n = 133) or 37°C (normothermic; n = 134), maintained using water-circulating thermal control pads. No active rewarming was used. Transcranial Doppler was used intraoperatively to monitor middle cerebral artery emboli. Neuropsychometric testing, consisting of a battery of 16 tests, was performed by blinded observers preoperatively, before discharge, and at 3 months, and tests were divided into 4 cognitive domains. A deficit was prospectively defined as a 1 standard deviation decrease in individual scores from baseline in 1 or more domains.
Results: The number of intraoperative cerebral emboli was similar between the control and the treated groups (188 [115–331] vs 182 [100–305], P = .71). At discharge, neurocognitive deficits were present in 45% of control patients and in 49% of treated patients (P = .49) and at 3 months decreased to 8% in control patients and 4% in treated patients (P = .28). There was no correlation between the total number of cerebral emboli and the occurrence of neurocognitive deficits (r = –0.01; P = .88). Hypothermic patients demonstrated trends toward reduced intensive care unit stay (1.4 ± 1.0 days vs 1.2 ± 0.7 days, P = .06) and increased chest tube output (655 ± 327 mL/24 h vs 584 ± 325 mL/24 h, P = .09).
Conclusions: Mild intraoperative hypothermia has no major adverse effects but does not decrease the incidence of neurocognitive deficits in patients undergoing coronary artery bypass surgery. In the absence of rewarming and cerebral hyperthermia, sustained mild hypothermia does not improve cognitive outcome.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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Postoperative cognitive deficits (POCDs), defined as impairments in memory, attention, and psychomotor function, are observed in 30% to 80% of patients after cardiac surgery.1
These deficits may be associated with distress for patients and families, delayed return to work and normal functioning, prolonged hospital stay, and reduced quality of life.2 Most important, the occurrence of POCDs has repeatedly been associated with late cognitive decline.3-5 Although a number of strategies have been proposed to reduce the occurrence of POCDs, no clear benefits have been demonstrated by clinical studies to date.
Evidence from animal studies has clearly demonstrated a large protective effect of mild hypothermia (2°C–5°C decrease in brain temperature) in the setting of global cerebral ischemia followed by reperfusion.6,7 This neuroprotective effect of mild hypothermia has also been observed in patients with out-of-hospital cardiac arrest.8 These studies have encouraged us to test the hypothesis that mild hypothermia minimizes neurologic injury in patients undergoing cardiac surgery.
The Warm Heart study first demonstrated the safety and potential benefits of normothermic coronary artery surgery with respect to myocardial preservation with no detrimental effects on neurologic outcome.9 Subsequent clinical trials have yielded conflicting results regarding the neuroprotective effects of hypothermia.10 In the majority of these studies, the duration of exposure to hypothermia was short and the treated (hypothermic) patients were often actively rewarmed with brain temperatures often exceeding 38°C, which may have adverse effects on neurocognitive outcome.11
We previously reported that, in patients undergoing coronary artery bypass surgery who were cooled to 32°C during cardiopulmonary bypass (CPB), rewarming to 34°C compared with 37°C was associated with a 23% reduction in the incidence of POCDs (P = .04).12 It was unclear whether the hypothermic group had benefited from a neuroprotective effect of mild hypothermia per se or from the lesser extent and rate of rewarming. Thus, in this study, we evaluated the neuroprotective effects of sustained mild hypothermia (34°C) maintained throughout the intraoperative period with no rewarming compared with effects of normothermia (37°C) in a similar population. We hypothesized that sustained mild hypothermia would lead to an even greater neuroprotective effect by extending the period of protection and avoiding any injury associated with rewarming on CPB.
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Materials and Methods |
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score < 11.5, or abnormal Modified Mini-Mental State scores) and serum creatinine greater than twice the normal level (normal range, men: 62-106 µmol/L; women: 35-88 µmol/L) were excluded. Patients undergoing repeat cardiac surgery were initially included, but soon after study initiation the selection criteria were modified to exclude these patients. Thus, only 4 patients with a history of cardiac surgery were included in the study.
Intraoperative Protocol and Randomization
Anesthesia induction and monitoring were performed as previously reported.14 After the induction of anesthesia, a temperature probe was placed in the nasopharynx, and this temperature was monitored and controlled throughout the intraoperative period. Bladder temperature was used as an indicator of visceral temperature.
Eligible and consenting patients were equally assigned to hypothermia or normothermia by using a computer-generated randomization list. Randomization was performed 30 minutes before the operation in blocks of 8 and stratified according to age more than 75 years. Treatment assignment was concealed in opaque, sealed envelopes that were assigned sequentially as patients were enrolled, according to age block.
Patients were unaware of the treatment assignment, which was not concealed from the clinical staff. Patients in the normothermic group were warmed with a forced-air heating blanket for 15 to 30 minutes before entering the operating room. Upon the patient’s arrival to the operating room, high-efficiency thermal pads were applied to the patient’s back and posterior aspect of the upper leg. The pads were connected to a water-circulating thermal control system (Arctic Sun; Medivance Corporation, Louisville, Colo), and cooling to 34°C or warming to 37°C was begun. Patients’ nasopharyngeal temperatures were kept as close as possible to 37°C or 34°C throughout the intraoperative period. CPB was performed via an ascending aortic cannula and a 2-stage right atrial cannula using membrane oxygenators and 43-µm arterial line filters (Cobe Cardiovascular, Arvada, Colo) maintaining a nonpulsatile flow at 2.5 to 2.8 L/min/m2. Mean arterial pressure was maintained between 50 and 80 mm Hg using phenylephrine or isoflurane. Blood gases were not temperature corrected. The heater/cooler was used only to make small corrections in temperature during CPB; the temperature of blood leaving the oxygenator was monitored and recorded and was not allowed to exceed 37.5°C or 34.5°C in the normothermic and hypothermic groups, respectively. After application of the aortic crossclamp, cardiac arrest was induced and maintained with antegrade cold crystalloid or blood cardioplegia.
Nasopharyngeal temperatures were kept constant at 34°C or 37°C until arrival to the intensive care unit (ICU). In the ICU, forced-air warming blankets were applied. Postoperative care, including blood product use, reexploration for bleeding, extubation, and ICU discharge, was conducted according to protocols previously described.14
Intraoperative Transcranial Doppler
Transcranial Doppler examinations were performed as previously described.15 Briefly, once the patient was asleep, bilateral 2-MHz pulsed-wave Doppler probes (sample volume: 10 mm) were secured on the temporal area using an adjustable headband (Marc 600; Spencer Technologies, Seattle, Wash) for continuous monitoring of the middle cerebral artery flow velocities. A dual-gated (separation: 5 mm), pulsed-wave transcranial Doppler system (DWL, Sipplingen, Germany,) recorded (dynamic range: 60 dB, overlapping: 58%), filtered (100 Hz), and stored both the Doppler waveforms and embolic signals (intensity threshold: 9 dB).
An ultrasonographer (R.A.R.), who was unaware of the cognitive findings and temperature treatment, reviewed the Doppler recording classified high-intensity transit signals (HITS) as true or equivocal on the basis of the acoustic and Doppler spectra characteristics of the embolus and the time delay caused by the embolus traveling between the 2 sample volumes.16 Artifacts and equivocal HITS were not included in the final analysis. The interobserver agreement in our center for discriminating between true HITS and artifacts using these Doppler characteristics has been reported to be excellent.15 The total count of HITS for each patient was the sum of bilateral counts recorded from the time of aortic cannulation until the removal of the aortic cannula after CPB. Only patients with successful bilateral Doppler recordings of the middle cerebral artery were included in the final analysis.
Neuropsychometric Evaluation
Neurologic status was assessed on the first postoperative day using the Canadian Neurological Scale.13 The National Institutes of Health Stroke Scale was administered preoperatively and 1 week and 3 months postoperatively.
We used conventional psychometric tests17 with empirically derived reliability and validity data, and included the core tests recommended by a consensus conference on assessment of neurobehavioral outcomes after cardiac surgery.18 Neurocognitive testing was performed at all time points under similar conditions and, whenever possible, by the same evaluator. Alternate forms were used to reduce learning effects. To optimize the reliability of the neuropsychometric evaluation, the psychometrists were trained and periodically audited by the same neuropsychologist. All patients were ambulating and fit for discharge at the time of postoperative assessment.
Learning efficiency and memory consolidation were evaluated with the Rey Auditory Verbal Learning Test. Psychomotor speed and dexterity, known to be a sensitive indicator of the presence of generalized brain dysfunction, was measured by the Trails A and B, Grooved Pegboard, and Symbol Digit Modalities Test (oral administration). Attentional capacity and control were evaluated using the revised Wechsler Adult Intelligence Scale Digit Span. To further evaluate this domain, we added the Mental Control Subtest of the Wechsler Memory Scale-III, in which the score reflects both speed and accuracy. Letter and Category Fluency was used to assess the speed and flexibility of verbal thought processes. To further evaluate the motor domain, finger tapping was evaluated on both hands.
Pre- and postoperative measures of mood (Geriatric Depression Scale) and anxiety (State-Trait Anxiety Inventory) were also recorded. The total battery required 60 minutes to administer. The Short Form Health Survey19 (SF-12) (QualityMetric Inc, Lincoln, RI) was administered preoperatively and 3 months postoperatively to assess health-related quality of life.
Safety End Points
Safety end points were recorded as previously described14 both during and after surgery and included nasopharyngeal, bladder, and oxygenator outlet temperatures, use of blood products, bleeding from chest tubes during 24 hours, use of inotropic and vasopressor drugs, time on CPB, and aortic crossclamp time. Furthermore, time until extubation, days in the ICU, and days in the hospital were noted. Myocardial infarction was defined as the appearance of new Q waves more than 0.04 seconds in duration in at least 2 contiguous leads. Creatine kinase was measured on the morning after surgery. Troponin T was determined if the total creatine kinase was greater than 800 U/L. Chest and leg wound infections were documented by the infection control service using established definitions.20
Statistical Analysis
Psychometric test results were analyzed both as continuous and dichotomous outcomes. Individual psychometric test scores yielded continuous measures repeated at 3 time points (preoperatively and 1-week and 3-month follow-ups). As such, individual scores were analyzed using mixed models to account for correlated repeated-measures data. The mixed models used an unstructured covariance matrix, and the model included a term for treatment and time-by-treatment interactions. No other covariates were added to the model.
To facilitate the categoric analysis, the psychometric tests were combined into 4 cognitive domains using factor analysis with orthogonal rotation as described by Newman and coworkers.4 This method reduced the individual test scores into 4 factors that were uncorrelated and accounted for 80% of the variance present in the test battery and approximately corresponded to the following areas of cognitive functioning: verbal memory, psychomotor speed and dexterity, attention, and motor function. The scores were adjusted so that an increase in score always indicated better performance, and a composite score, intended to represent overall cognitive performance, was formed by summing the 4 individual factors (composite cognitive index). A patient was deemed to have had a cognitive deficit if 1 or more factor scores decreased by at least 1 standard deviation. A secondary analysis was performed using the reliable change index methodology to account for practice effects. A cohort of 75 nonsurgical control subjects with coronary artery disease were tested at the same intervals as well as patients, and this information was used to adjust for practice effects in the study patients as described by Rasmussen and colleagues.21
Data are presented as mean ± standard deviation or median (interquartile range). Continuous variables were compared by using unpaired t tests if normally distributed or the Wilcoxon rank–sum test for non-normally distributed variables. Categoric data, including the primary end point of POCD incidence, were compared by using a chi-square test. The Fisher exact test was used when an expected cell count was less than 5. The primary analysis was by treatment group (normothermia or hypothermia), with no exclusions.
Sample Size
A prospectively performed sample size calculation indicated that the sample size of 300 patients provides 80% power (with 
= 0.05) to detect a 27% difference in incidence of POCDs given a rate of 60% in the control group. The study was terminated after 267 patients had been randomized as funds were exhausted.
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Results |
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Neurocognitive Outcome
Table 3
depicts the results of the neurocognitive tests and factor-based analyses. Overall, there was a decline in performance on neurocognitive tests at the predischarge time point with some recovery at 3 months. However, time-by-treatment interactions (indicating differential changes over time between groups) were nonsignificant for all tests except for Digits Backward (P = .008), which demonstrated improved scores for hypothermic patients both at discharge and at 3-month follow-up. A significant difference favoring hypothermia was also seen in the attention domain (P = .03), likely driven by the difference in the Digits Backward test result. However, after adjustment for multiple comparisons these differences were not statistically significant.
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Quality of Life
Quality of life, evaluated using the SF-12,19 was similar between groups, both in the Physical and Mental domains, at baseline and at 3 months. There was a significant increase in self-reported quality of life after surgery. Compared with those of patients at baseline, patients with neurocognitive deficits at discharge demonstrated a smaller improvement in the Mental component of the SF-12 (P = .03) but not in the Physical component (P = .70) at 3 months.
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Discussion |
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In a previous study,12 we examined the effect of hypothermia in cardiac surgical patients who were cooled to 32°C and then randomized to rewarming (avoiding cerebral hyperthermia) to 34°C or 37°C. We found that mild hypothermia in this setting led to a statistically significant and clinically relevant 23% reduction in the early incidence of POCDs, as well as a highly significant and consistent difference in performance on the grooved pegboard test at 3 months. We hypothesized that sustained mild hypothermia would lead to an even greater neuroprotective effect by extending the period of protection and avoiding any injury associated with rewarming on CPB. We did not detect a significant difference in neuropsychologic outcome between groups in this study. Given the similar study conditions, patient populations, and outcome measures between the 2 studies, the absence of benefit suggests that mild hypothermia per se was not responsible for the lower incidence of POCDs in the earlier study. Rewarming (32°C–37°C during a period of 10–15 minutes), even in the absence of hyperthermia, was likely responsible for worse neurocognitive outcome in the normothermic group in the previous study (Figure 2).
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largely because of the absence of adequately powered randomized clinical trials to provide guidance in this area. A recent evidence-based review that discussed temperature management during CBP practices suggested limiting the arterial line temperature to 37°C to avoid cerebral hyperthermia as a class IIa recommendation.10 However, no specific recommendations were given with respect to hypothermia and rewarming. The findings of this study challenge the conventional thinking that mild intraoperative hypothermia in cardiac surgical patients is neuroprotective. Furthermore, taken together, evidence from our 2 clinical trials suggests that rapid rewarming is associated with increased neurocognitive deficits. Thus, the temperature at which patients are maintained is less important as long as cerebral hyperthermia and rapid rewarming are avoided. It is important to note that these data cannot be generalized to the setting of mild hypothermia in the context of ischemic brain injury caused by atheromatous emboli or hypoperfusion. Should the clinician decide to use mild hypothermia to reduce ischemic injury on the basis of laboratory evidence and its efficacy in the setting of cardiac arrest, our data suggest that it is without serious adverse effects in patients who are at low risk of bleeding.
Our previously published interim safety analysis demonstrated the safety of deliberate, sustained, mild hypothermia in cardiac surgery patients.14 The final analysis of safety end points in these patients corroborates our previous report. The incidence of clinically significant bleeding was similar between groups, as suggested by equivalent rates of reexploration and blood product use. Chest tube losses were nonsignificantly higher in hypothermic patients by approximately 70 mL per patient. Surprisingly, the length of stay in the ICU was slightly shorter in hypothermic patients, a trend that did not reach statistical significance. The incidence of perioperative myocardial infarction and serum troponin levels were both similar between groups. We found that the 3-month incidence of POCDs was higher in the normothermic patients compared with hypothermic patients (8% vs 4%, respectively, P = .28). Although this represents a relative risk reduction of 50% with hypothermia, it is only an absolute risk reduction of 4%, and this study was not powered to detect such a small difference at the 3-month follow-up. Thus, deliberate sustained intraoperative and perioperative hypothermia and sustained normothermia are both safe in this low-risk population of patients undergoing coronary artery bypass grafting.
Although atherosclerotic macroemboli arising from the ascending aorta are clearly a source of postoperative stroke, the relationship between intraoperative cerebral microemboli and POCDs continues to be debated. The presence of fat emboli in the brain has been demonstrated at autopsy after cardiac surgery.23,24 In our study, there was no difference in the number of HITS between the hypothermic and normothermic groups. More important, the total number of HITS did not correlate with postoperative neurocognitive function in the total cohort of 188 patients with high-quality transcranial Doppler recordings. This lack of correlation may be due to the inability of transcranial Doppler to differentiate between the relatively benign air emboli from the more damaging fat and atherosclerotic debris. This finding also brings into question whether microemboli are, in fact, the source of neurologic injury or whether other proposed mechanisms, such as systemic inflammation, cerebral edema, and global hypoperfusion, are responsible. Other groups have also reported a lack of correlation between POCDs and cerebral ischemia detected by diffusion-weighted magnetic resonance imaging.25 Last, a number of studies have identified various preoperative patient characteristics (eg, age, education level, serum creatinine level, left ventricular function, and other variables) that are predictive of postoperative cognitive dysfunction.26-28 It may be that the stress of surgery is not causal but merely unmasks preexisting cerebrovascular disease and identifies the patients who are predisposed to future cognitive decline. POCDs may therefore be a marker of subtle preoperative cognitive changes and not evidence of intraoperative or perioperative cerebral injury. This suggestion would explain the disappearance of most deficits 3 months and 1 year after surgery with reappearance 5 years later.3-5
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Conclusions |
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Acknowledgments |
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Footnotes |
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References |
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